The role of postsynaptic muscle fibers in maintenance and repair of mammalian neuromuscular junctions

Previous studies from our lab showed that terminal Schwann cells (TSCs) are actively involved in the restoration of functional synapses during reinnervation at mammalian neuromuscular junctions (NMJs). However, it is unclear what induces TSCs to extend processes that guide the nerve growth (Son and Thompson, 1995a,b). Is it the loss of the axon or instead, some signal arising from denervated muscle fibers? The main objective of my dissertation was to examine whether muscle fibers can be the source of signals affecting TSC growth. In Chapter 2, I report that both TSCs and nerve terminals are maintained at the former junction even after their underlying muscle fiber degenerates. Some of the original AChRs are surprisingly sustained at the synaptic sites for a long time with the preserved pretzel pattern. These results show that the postsynaptic target is not necessary for the maintenance of presynaptic structures. In Chapter 3, I report that following fiber regeneration, newly formed AChRs are clearly separated from the persisting receptors at most locations and they are apposed by the nerves. Moreover, as the fiber regenerates, TSCs begin to grow processes. Nerve sprouts then follow these processes to form new synaptic sites beyond the old receptor territory. My observations therefore show that signals for nerve growth arise from regenerating fibers and they appear to act by first affecting TSCs. Such signals seem diffusible because I saw that TSCs on surrounding fibers also began to grow during regeneration. In Chapter 4, I report that new junctions on the regenerated fibers are very dynamic. They undergo continual remodeling and eventually take on an 'en grappe' pattern. Since the synapses on undamaged fibers are normally very stable, these observations suggest that regeneration has set in place a process whereby the synapses are unable to stabilize. Interestingly, this appears to be the case in muscles that degenerate as a consequence of muscular dystrophy. My findings are important because they suggest an active role of the postsynaptic muscle fiber not in synapse maintenance but rather in generating signals that attract innervation after injury.